9-135784568-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_020822.3(KCNT1):c.2977C>T(p.Arg993Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000977 in 1,535,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R993Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.583

Publications

1 publications found

Variant links:

Genes affected

KCNT1 (HGNC:18865): (potassium sodium-activated channel subfamily T member 1) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

KCNT1 Gene-Disease associations (from GenCC):

childhood-onset epilepsy syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 14
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
malignant migrating partial seizures of infancy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
autosomal dominant nocturnal frontal lobe epilepsy 5
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.2977C>T	p.Arg993Trp	missense_variant	Exon 26 of 31	ENST00000371757.7	NP_065873.2	Q5JUK3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 link	c.2977C>T	p.Arg993Trp	missense_variant	Exon 26 of 31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

145198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000300

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000255

AC:

AN:

234954

AF XY:

0.0000234

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000572

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000935

AC:

AN:

1390024

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

690800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31074

American (AMR)

AF:

0.00

AC:

AN:

42170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23220

East Asian (EAS)

AF:

0.0000571

AC:

AN:

35012

South Asian (SAS)

AF:

0.00

AC:

AN:

84628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3974

European-Non Finnish (NFE)

AF:

0.0000103

AC:

AN:

1068834

Other (OTH)

AF:

0.00

AC:

AN:

55724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000138

AC:

AN:

145198

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

70388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39108

American (AMR)

AF:

0.00

AC:

AN:

14426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

4700

South Asian (SAS)

AF:

0.00

AC:

AN:

4404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

66700

Other (OTH)

AF:

0.00

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5

Uncertain:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 993 of the KCNT1 protein (p.Arg993Trp). This variant is present in population databases (rs368252006, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 473379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

May 29, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in a patient with a rare disease; however, no specific clinical information was provided (PMID: 33726816); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33726816) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

.;.;.;.;.;.;.;.;D;.

Eigen

Benign

0.13

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.18

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.3

.;.;.;.;.;.;.;.;M;.

PhyloP100

0.58

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.9

.;.;D;.;.;.;.;.;D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

.;.;D;.;.;.;.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;.;.;.;.;D;.

Vest4

0.97

MVP

0.86

MPC

1.7

ClinPred

0.81

GERP RS

0.56

Varity_R

0.82

gMVP

0.97

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over